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Hypersomnolence is characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassification (ISCD-3) distinguishes between three main subtypes: narcolepsy type 1 (with cataplexy), narcolepsy type 2 (without cataplexy), and idiopathic hypersomnia (IH; with or without long sleep time) (Khan and Trotti 2015; Contemporary Reviews in Sleep Medicine, pp. 262-273).
Excessive Daytime Sleeping (EDS) is the principal feature of the central disorders of hypersomnolence. EDS is defined as the inability to stay awake and alert during major waking episodes of the day, resulting in periods of irrepressible need for sleep or unintended lapses into drowsiness or sleep. The Epworth Sleepiness Scale (ESS) is widely used in the field of sleep medicine as a subjective measure of a patient's sleepiness (Johns 1991; Sleep, 14(6), pp. 540-545). The total ESS score can range from zero to 24 with higher scores correlating with increasing degrees of sleepiness. A score greater than 10 is consistent with excessive sleepiness. The mean ESS score is approximately six among healthy adults, compared to 16 or greater among patients with narcolepsy or idiopathic hypersomnia.
Idiopathic hypersomnia (also known as idiopathic hypersomnolence) is a sleep disorder that is characterized by chronic excessive daytime sleepiness (daily periods of irrepressible need to sleep or daytime lapses into sleep) and often difficulty waking up from nocturnal sleep or daytime naps (sleep inertia). Unlike narcolepsy, spontaneous remission has been reported in 14% to 25% of patients with IH (Vernet and Arnulf 2009; Sleep, 32(6); pp. 753-759). IH is associated with several somatic symptoms and comorbid conditions (Sowa et al. Phsychosomatics, 2016, 57(2), pp. 152-164). Memory difficulties (79%), attentional difficulties (55%), chronic headache (52.8%), and excessive sweating (34.7%) are particularly prominent and depression is present in 15.1% of patients. The condition is disabling, sometimes even more so than narcolepsy type 1 or 2. (Billiard and Sonka; Sleep Medicine Reviews, 29, 2016; pp. 23-33). Initially, complications of idiopathic hypersomnia may appear similar to those of narcolepsy type 1 or 2, including poor performance at school and work, sleep during recreational activities and a higher incidence of car accidents. However, some idiopathic hypersomnia patients experience unique and often debilitating complaints including the absence of benefit from nocturnal sleep and daytime naps to the extent that they never feel refreshed, difficulty in awakening and resistance to stimulant medications (Singh M, Drake C L, Roth T; The prevalence of multiple sleep-onset REM periods in a population-based sample; Sleep, 2006, 29(7), pp. 890-895). These issues can make it difficult to pursue a normal lifestyle and put pressure on the sufferer's work and family relationships.
There is some debate in the literature regarding the underlying causes of hypersomnolence. Rye et al. (Sci. Transl. Med., 2012; 4:161) have suggested that a naturally-occurring substance in cerebrospinal fluid (CSF) augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness. However, Dauvilliers et al. (Ann. Neurol., 2016. 80(2): pp. 259-268, concluded that CSF GABAA receptor activity does not appear to be a useful biomarker for assessing the etiology or severity of centrally-mediated hypersomnolence disorders, including idiopathic hypersomnia.
More recently, Moody, O. A., et al. (Ann. Neurol, 2017, doi: 10.1002/ana.24940) have refuted the findings of Dauvilliers et al. and have demonstrated reproducible GABAA receptor enhancement in 32 novel CSF samples. Moody et al. suggest that Dauvilliers and colleague's inability to do so is attributable to flaws in their experimental design. However, Dauvilliers, Y et al. (Ann Neurol, 2017; doi:10.1002/ana.24939), have again disagreed with the findings of Moody et al., and published a defence of their study and conclusions.
Thus, the etiology of hypersomnolence disorders, such as idiopathic hypersomnia, remains unclear.
This notwithstanding, treatments that act as GABA antagonists, e.g. flumazenil and clarithromycin, have shown some promise for the treatment of idiopathic hypersomnia, although their use is still experimental (see, for example Kelty et al., Journal of Psychopharmacology, 2014, 28(7), 703-706 and Trotti et al., Journal of Psychopharmacology, 2014, 28(7), 697-702).
US 2011/0028418 discloses a method of treating GABAA receptor mediated hypersomnia and excessive sleepiness associated with GABAA receptor mediated hypersomnia by using flumazenil.
WO 2015/160766 discloses a method of treating hypersomnia by administering GABAA chloride channel blockers such as pentylenetetrazole (PTZ), bilobalide (BB), penicillin and ginkolide B.
There are currently no approved therapies for idiopathic hypersomnia, although several generic treatments are used as compassionate medications (off-label), such as modafinil (branded under e.g. the trademark PROVIGIL® ((modafinil) and amphetamine derivatives, which primarily are FDA/EMA approved wake-promoting narcolepsy medications. Sodium oxybate (branded under e.g. the trademark XYREM® (sodium oxybate)) is also used off-label as a second/third line treatment. However, the treatment options currently available for idiopathic hypersomnia are often unsatisfactory, with suboptimal efficacy, troublesome side effects, development of drug tolerance, and inconvenience. There is therefore a need for a safe and effective drug for the treatment of idiopathic hypersomnia.
3α-ethynyl-3β-hydroxy-5α-androstan-17-one oxime is disclosed in WO 2008/063128 and is known to act as an antagonist to the positive allosteric modulation of GABAA receptors by endogenous neurosteroids including allopregnanolone and tetrahydrodeoxycorticosterone (THDOC). This compound is disclosed for the treatment of hepatic encephalopathy in WO 2015/114308.